Journal of NeuroVirology

, 17:382

Osteopontin enhances HIV replication and is increased in the brain and cerebrospinal fluid of HIV-infected individuals

  • Amanda Brown
  • Tanzeem Islam
  • Robert Adams
  • Sujata Nerle
  • Masiray Kamara
  • Caitlin Eger
  • Karen Marder
  • Bruce Cohen
  • Giovanni Schifitto
  • Justin C. McArthur
  • Ned Sacktor
  • Carlos A. Pardo
Article

Abstract

Despite effective and widely available suppressive anti-HIV therapy, the prevalence of mild neurocognitive dysfunction continues to increase. HIV-associated neurocognitive disorder (HAND) is a multifactorial disease with sustained central nervous system inflammation and immune activation as prominent features. Inflammatory macrophages, HIV-infected and uninfected, play a central role in the development of HIV dementia. There is a critical need to identify biomarkers and to better understand the molecular mechanisms leading to cognitive dysfunction in HAND. In this regard, we identified through a subtractive hybridization strategy osteopontin (OPN, SPP1, gene) an inflammatory marker, as an upregulated gene in HIV-infected primary human monocyte-derived macrophages. Knockdown of OPN in primary macrophages resulted in a threefold decrease in HIV-1 replication. Ectopic expression of OPN in the TZM-bl cell line significantly enhanced HIV infectivity and replication. A significant increase in the degradation of the NF-κB inhibitor, IκBα and an increase in the nuclear-to-cytoplasmic ratio of NF-κB were found in HIV-infected cells expressing OPN compared to controls. Moreover, mutation of the NF-κB binding domain in the HIV-LTR abrogated enhanced promoter activity stimulated by OPN. Interestingly, compared to cerebrospinal fluid from normal and multiple sclerosis controls, OPN levels were significantly higher in HIV-infected individuals both with and without neurocognitive disorder. OPN levels were highest in HIV-infected individuals with moderate to severe cognitive impairment. Moreover, OPN was significantly elevated in brain tissue from HIV-infected individuals with cognitive disorder versus those without impairment. Collectively, these data suggest that OPN stimulates HIV-1 replication and that high levels of OPN are present in the CNS compartment of HIV-infected individuals, reflecting ongoing inflammatory processes at this site despite anti-HIV therapy.

Keywords

HIV-associated neurocognitive disorder CD44 Nef 

Supplementary material

13365_2011_35_MOESM1_ESM.doc (48 kb)
Table 2Clinical Characteristics of Brain Tissue Samples (DOC 47 kb)

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Copyright information

© Journal of NeuroVirology, Inc. 2011

Authors and Affiliations

  • Amanda Brown
    • 1
  • Tanzeem Islam
    • 1
  • Robert Adams
    • 1
  • Sujata Nerle
    • 1
  • Masiray Kamara
    • 1
  • Caitlin Eger
    • 1
  • Karen Marder
    • 2
  • Bruce Cohen
    • 3
  • Giovanni Schifitto
    • 4
  • Justin C. McArthur
    • 1
  • Ned Sacktor
    • 1
  • Carlos A. Pardo
    • 1
  1. 1.Department of NeurologyJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Neurology, Psychiatry, Sergievsky Center and Taub Institute on Alzheimer’s Disease and the Aging Brain, New York Presbyterian HospitalColumbia University College of Physicians and SurgeonsNew YorkUSA
  3. 3.Department of NeurologyNorthwestern University Feinberg School of MedicineChicagoUSA
  4. 4.Department of Neurology, School of Medicine and DentistryUniversity of RochesterRochesterUSA

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